The importance of modelling heterogeneity in complex disease: application to NIMH Schizophrenia Genetics Initiative data

As for other complex diseases, linkage analyses of schizophrenia (SZ) have produced evidence for numerous chromosomal regions, with inconsistent results reported across studies. The presence of locus heterogeneity appears likely and may reduce the power of linkage analyses if homogeneity is assumed. In addition, when multiple heterogeneous datasets are pooled, intersample variation in the proportion of linked families ( a) may diminish the power of the pooled sample to detect susceptibility loci, in spite of the larger sample size obtained. We compare the significance of linkage. findings obtained using allele- sharing LOD scores ( LODexp) - which assume homogeneity - and heterogeneity LOD scores ( HLOD) in European American and African American NIMH SZ families. We also pool these two samples and evaluate the relative power of the LODexp and two different heterogeneity statistics. One of these ( HLOD- P) estimates the heterogeneity parameter a only in aggregate data, while the second ( HLOD- S) determines a separately for each sample. In separate and combined data, we show consistently improved performance of HLOD scores over LODexp. Notably, genome-wide significant evidence for linkage is obtained at chromosome 10p in the European American sample using a recessive HLOD score. When the two samples are combined, linkage at the 10p locus also achieves genome-wide significance under HLOD- S, but not HLOD- P. Using HLOD- S, improved evidence for linkage was also obtained for a previously reported region on chromosome 15q. In linkage analyses of complex disease, power may be maximised by routinely modelling locus heterogeneity within individual datasets, even when multiple datasets are combined to form larger samples.

The positive impact of multiple sclerosis (MS) on carers: Associations between carer benefit finding and positive and negative adjustment domains

Purpose. This study examined benefit finding in MS carers including the dimensionality of benefit finding, relations between carer and care recipient benefit finding, and the effects of carer benefit finding on carer positive and negative adjustment domains. Method. A total of 267 carers and their care recipients completed questionnaires at Time 1 and 3 months later, Time 2 (n=155). Illness data were collected at Time 1, and number of problems, stress appraisal, benefit finding, negative (global distress, negative affect) and positive (life satisfaction, positive affect, dyadic adjustment) adjustment domains were measured at Time 2. Results. Qualitative data revealed seven benefit finding themes, two of which were adequately represented by the Benefit Finding Scale (BFS) [1] (Mohr et al. Health Psychology 1999; 18: 376). Factor analyses indicated two factors (Personal Growth, Family Relations Growth) which were psychometrically sound and showed differential relations with illness and adjustment domains. Although care recipients reported higher levels of benefit finding than carers, their benefit finding reports regarding personal growth were correlated. The carer BFS factors were positively related to carer and care recipient dyadic adjustment. Care recipient benefit finding was unrelated to carer adjustment domains. After controlling for the effects of demographics, care recipient characteristics, problems and appraisal, carer benefit finding was related to carer positive adjustment domains and unrelated to carer negative adjustment domains. Conclusion. Findings support the role of benefit finding in sustaining positive psychological states and the communal search for meaning within carer-care recipient dyads.

Benthic metabolism as an indicator of stream ecosystem health

We tested direct and indirect measures of benthic metabolism as indicators of stream ecosystem health across a known agricultural land-use disturbance gradient in southeast Queensland, Australia. Gross primary production (GPP) and respiration (R-24) in benthic chambers in cobble and sediment habitats, algal biomass (as chlorophyll a) from cobbles and sediment cores, algal biomass accrual on artificial substrates and stable carbon isotope ratios of aquatic plants and benthic sediments were measured at 53 stream sites, ranging from undisturbed subtropical rainforest to catchments where improved pasture and intensive cropping are major land-uses. Rates of benthic GPP and R-24 varied by more than two orders of magnitude across the study gradient. Generalised linear regression modelling explained 80% or more of the variation in these two indicators when sediment and cobble substrate dominated sites were considered separately, and both catchment and reach scale descriptors of the disturbance gradient were important in explaining this variation. Model fits were poor for net daily benthic metabolism (NDM) and production to respiration ratio (P/R). Algal biomass accrual on artificial substrate and stable carbon isotope ratios of aquatic plants and benthic sediment were the best of the indirect indicators, with regression model R-2 values of 50% or greater. Model fits were poor for algal biomass on natural substrates for cobble sites and all sites. None of these indirect measures of benthic metabolism was a good surrogate for measured GPP. Direct measures of benthic metabolism, GPP and R-24, and several indirect measures were good indicators of stream ecosystem health and are recommended in assessing process-related responses to riparian and catchment land use change and the success of ecosystem rehabilitation actions.

Critical health psychology - Who benefits?

This commentary deals with two issues raised by Hepworth (this issue). Concerning definitions, it argues that critical health psychology needs to be more explicit in defining itself as politically left-wing, and that its central defining characteristic should be that it is research and practice which aims primarily to benefit the participants, regardless of any specific method or epistemology. Concerning the value of critical health psychology, it argues that work which has improved health on a global scale and which aims to reduce inequities is being done, but not by critical psychologists, and suggests a need for more action and less rhetoric.

Development of a dosage strategy in patients receiving enoxaparin by continuous intravenous infusion using modelling and simulation

Aim To develop an appropriate dosing strategy for continuous intravenous infusions (CII) of enoxaparin by minimizing the percentage of steady-state anti-Xa concentration (C-ss) outside the therapeutic range of 0.5-1.2 IU ml(-1). Methods A nonlinear mixed effects model was developed with NONMEM (R) for 48 adult patients who received CII of enoxaparin with infusion durations that ranged from 8 to 894 h at rates between 100 and 1600 IU h(-1). Three hundred and sixty-three anti-Xa concentration measurements were available from patients who received CII. These were combined with 309 anti-Xa concentrations from 35 patients who received subcutaneous enoxaparin. The effects of age, body size, height, sex, creatinine clearance (CrCL) and patient location [intensive care unit (ICU) or general medical unit] on pharmacokinetic (PK) parameters were evaluated. Monte Carlo simulations were used to (i) evaluate covariate effects on C-ss and (ii) compare the impact of different infusion rates on predicted C-ss. The best dose was selected based on the highest probability that the C-ss achieved would lie within the therapeutic range. Results A two-compartment linear model with additive and proportional residual error for general medical unit patients and only a proportional error for patients in ICU provided the best description of the data. Both CrCL and weight were found to affect significantly clearance and volume of distribution of the central compartment, respectively. Simulations suggested that the best doses for patients in the ICU setting were 50 IU kg(-1) per 12 h (4.2 IU kg(-1) h(-1)) if CrCL < 30 ml min(-1); 60 IU kg(-1) per 12 h (5.0 IU kg(-1) h(-1)) if CrCL was 30-50 ml min(-1); and 70 IU kg(-1) per 12 h (5.8 IU kg(-1) h(-1)) if CrCL > 50 ml min(-1). The best doses for patients in the general medical unit were 60 IU kg(-1) per 12 h (5.0 IU kg(-1) h(-1)) if CrCL < 30 ml min(-1); 70 IU kg(-1) per 12 h (5.8 IU kg(-1) h(-1)) if CrCL was 30-50 ml min(-1); and 100 IU kg(-1) per 12 h (8.3 IU kg(-1) h(-1)) if CrCL > 50 ml min(-1). These best doses were selected based on providing the lowest equal probability of either being above or below the therapeutic range and the highest probability that the C-ss achieved would lie within the therapeutic range. Conclusion The dose of enoxaparin should be individualized to the patients' renal function and weight. There is some evidence to support slightly lower doses of CII enoxaparin in patients in the ICU setting.

Multi-level zero-inflated Poisson regression modelling of correlated count data with excess zeros

Count data with excess zeros relative to a Poisson distribution are common in many biomedical applications. A popular approach to the analysis of such data is to use a zero-inflated Poisson (ZIP) regression model. Often, because of the hierarchical Study design or the data collection procedure, zero-inflation and lack of independence may occur simultaneously, which tender the standard ZIP model inadequate. To account for the preponderance of zero counts and the inherent correlation of observations, a class of multi-level ZIP regression model with random effects is presented. Model fitting is facilitated using an expectation-maximization algorithm, whereas variance components are estimated via residual maximum likelihood estimating equations. A score test for zero-inflation is also presented. The multi-level ZIP model is then generalized to cope with a more complex correlation structure. Application to the analysis of correlated count data from a longitudinal infant feeding study illustrates the usefulness of the approach.

PRN Sedation-patterns of prescribing and administration in a child and adolescent mental health inpatient service

Objective: To identify utilisation rates of prn (pro re nata) sedation in children and adolescents receiving inpatient psychiatric treatment, and to compare correlates of prn prescribing and administration. Method A retrospective chart review examined 122 medical charts from a child and youth mental health inpatient service. Results 71.3% of patients were prescribed prn sedation and 50.8% were administered prn sedation. Patients received an average of 8.0 doses of prn sedation, with 9.8% receiving 10 or more doses. Chlorpromazine and diazepam were the most commonly utilised agents. Prescribing of prn sedation was only related to use of regular medications (p < 0.01), and non-parent carers (p < 0.01). In contrast, administration of prn sedation was associated with multiple diagnoses (p < 0.01), pervasive development disorder (p < 0.01), mental retardation (p < 0.01) ADHD (p < 0.01), longer hospital admission (p < 0.01), use of atypical antipsychotics (p < 0.01) and polypharmacy (p < 0.01). Conclusions Despite lack of data to inform practice, prn sedation is widely utilised, especially in complex patients. Future research in this area needs to incorporate nurses and examine whether patients benefit from prn sedation, which drugs and dosing patterns optimise safety and efficacy, and what is the role of prn sedation in the context of other medication.

Smoking and schizophrenia: is symptom profile related to smoking and which antipsychotic medication is of benefit in reducing cigarette use?

Smoking rate is disproportionately high among patients with schizophrenia, resulting in significant morbidity and mortality. However, cigarette smoking has been reported to have beneficial effects on negative symptoms, extrapyramidal symptoms, cognitive functioning and mood symptoms. Therefore, smoking cessation may worsen disability in schizophrenia. The association between smoking and these key clinical parameters was examined. Additionally, severity of smoking across four different antipsychotic treatment groups was explored. One hundred and forty-six patients with schizophrenia were assessed for smoking using expired carbon monoxide and smoking history. They were administered the Positive and Negative Symptom Scale, The Extrapyramidal Symptom Rating Scale, the Barnes Akathisia Rating Scale, Reitans Trail-making Test (A and B) and General Health Questionnaire-28. There was no difference in the chlorpromazine equivalent dose of any of the medications studied. Atypical agents were associated with significantly lower levels of smoking when compared with typical medications. There was no difference in smoking severity between the individual atypical medications examined. Similarly, there were no significant differences between smoking and non-smoking groups with regard to Positive and Negative Symptom Scale, Extrapyramidal Symptom Rating Scale, Trail-making Test and General Health Questionnaire-28. However, there was a significant difference between these groups with the smoking group demonstrating less akathisia. Smoking is not associated with positive, negative cognitive and mood symptoms in schizophrenia. Smoking is associated with lower levels of antipsychotic induced akathisia. Clinicians should not be discouraged from helping patients stop smoking for fear of worsening symptoms. However, akathisia may emerge upon cessation of smoking. Switching patients from typical to atypical antipsychotics may assist patients with schizophrenia to give up smoking.

The effect of personal characteristics on the validity of nutrient intake estimates using a food-frequency questionnaire

Objective: To assess validity of the Nambour food-frequency questionnaire (FFQ) relative to weighed food records (WFRs), and the extent to which selected demographic, anthropometric and social characteristics explain differences between the two dietary methods. Design: Inter-method validity study; 129-item FFQ vs. 12 days of WFR over 12 months. Setting: Community-based Nambour Skin Cancer Prevention Trial. Subjects: One hundred and fifteen of 168 randomly selected participants in the trial (68% acceptance rate) aged 25-75 years. Results: Spearman correlations between intakes from the two methods ranged from 0.18 to 0.71 for energy-adjusted values. Differences between FFQ and WFR regressed on personal characteristics were significantly associated with at least one characteristic for 16 of the 21 nutrients. Sex was significantly associated with differences for nine nutrients; body mass index (BMI), presence of any medical condition and age were each significantly associated with differences for three to six nutrients; use of dietary supplements and occupation were associated with differences for one nutrient each. There was no consistency in the direction of the significant associations. Regression models explained from 7% (riboflavin) to 27% (saturated fat) of variation in differences in intakes. Conclusions: The relative validity of FFQ estimates for many nutrients is quite different for males than for females. Age, BMI, medical condition and level of intake were also associated with relative validity for some nutrients, resulting in the need to adjust intakes estimates for these in modelling diet-disease relationships. Estimates for cholesterol, beta-carotene equivalents, retinol equivalents, thiamine, riboflavin and calcium would not benefit from this.

Using epidemiological models to estimate the health effects of diet behaviour change: the example of tailored fruit and vegetable promotion

Objective: To explore the use of epidemiological modelling for the estimation of health effects of behaviour change interventions, using the example of computer-tailored nutrition education aimed at fruit and vegetable consumption in The Netherlands. Design: The effects of the intervention on changes in consumption were obtained from an earlier evaluation study. The effect on health outcomes was estimated using an epidemiological multi-state life table model. input data for the model consisted of relative risk estimates for cardiovascular disease and cancers, data on disease occurrence and mortality, and survey data on the consumption of fruits and vegetables. Results: if the computer-tailored nutrition education reached the entire adult population and the effects were sustained, it could result in a mortality decrease of 0.4 to 0.7% and save 72 to 115 life-years per 100000 persons aged 25 years or older. Healthy life expectancy is estimated to increase by 32.7 days for men and 25.3 days for women. The true effect is likely to lie between this theoretical maximum and zero effect, depending mostly on durability of behaviour change and reach of the intervention. Conclusion: Epidemiological models can be used to estimate the health impact of health promotion interventions.